Abstract
Background and aimsWe aimed at investigating the role of 14q32 microRNAs in intimal hyperplasia and accelerated atherosclerosis; two major contributors to restenosis. Restenosis occurs regularly in patients treated for coronary artery disease and peripheral arterial disease. We have previously shown that inhibition of 14q32 microRNAs leads to increased post-ischemic neovascularization, and microRNA miR-494 also decreased atherosclerosis, while increasing plaque stability. We hypothesized that 14q32 microRNA inhibition has beneficial effects on intimal hyperplasia, as well as accelerated atherosclerosis. MethodsNon-constrictive cuffs were placed around both femoral arteries of C57BL/6J mice to induce intimal hyperplasia. Accelerated atherosclerotic plaque formation was induced in hypercholesterolemic ApoE−/− mice by placing semi-constrictive collars around both carotid arteries. 14q32 microRNAs miR-329, miR-494 and miR-495 were inhibited in vivo using Gene Silencing Oligonucleotides (GSOs). ResultsGSO-495 administration led to a 32% reduction of intimal hyperplasia. Moreover, the number of macrophages in the arterial wall of mice treated with GSO-495 was reduced by 55%. Inhibition of miR-329 and miR-494 had less profound effects on intimal hyperplasia. GSO-495 administration also decreased atherosclerotic plaque formation by 52% and plaques of GSO-495 treated animals showed a more stable phenotype. Finally, cholesterol levels were also decreased in GSO-495 treated animals, via reduction of the VLDL-fraction. ConclusionsGSO-495 administration decreased our primary outcomes, namely intimal hyperplasia, and accelerated atherosclerosis. GSO-495 administration also favourably affected multiple secondary outcomes, including macrophage influx, plaque stability and total plasma cholesterol levels. We conclude that 14q32 microRNA miR-495 is a promising target for prevention of restenosis.
Highlights
Expression levels of 14q32 microRNAs miR-329, miR-494 and miR-495 were measured in the femoral arteries of wildtype C57BL/ 6J mice and the carotid arteries of ApoEÀ/À mice, representing the two models used to study post-interventional intimal hyperplasia
At 21 days after cuff placement, intimal hyperplasia was significantly reduced by 33% following treatment with Gene Silencing Oligonucleotides (GSOs)-495 compared to GSO-control
GSO-329 treatment significantly increased luminal area and decreased lumenstenosis in these animals (Supplemental Fig. 1B and C). These data show a beneficial effect of GSO-495 treatment on intimal hyperplasia in C57BL/6J mice
Summary
Leukocytes adhere to and infiltrate the vessel wall These leukocytes secrete inflammatory cytokines and chemokines promoting inflammation, and release matrix metalloproteinases and growth factors leading to extracellular matrix remodelling as well as smooth muscle cell (SMC) proliferation and migration. Accelerated atherosclerosis is initiated by severe flow disturbance combined with the uptake of lipids by macrophages in the vessel wall and subsequent formation of foam cells under hypercholesterolemic conditions. We aimed at investigating the role of 14q32 microRNAs in intimal hyperplasia and accelerated atherosclerosis; two major contributors to restenosis. We hypothesized that 14q32 microRNA inhibition has beneficial effects on intimal hyperplasia, as well as accelerated atherosclerosis. Accelerated atherosclerotic plaque formation was induced in hypercholesterolemic ApoEÀ/À mice by placing semi-constrictive collars around both carotid arteries. Conclusions: GSO-495 administration decreased our primary outcomes, namely intimal hyperplasia, and accelerated atherosclerosis. We conclude that 14q32 microRNA miR-495 is a promising target for prevention of restenosis
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